Our results of adverse obstetric and perinatal outcomes after procedural FET are similar to those of some recently published studies [11–13, 15, 16]. In our study we were able to adjust for maternal age, infertility duration, cause of infertility, BMI, endometrial thickness and high-quality embryo transfer rate. And to reduce the influence of confounding factors, only singletons were included. In the multiple logistic regression analysis, we illustrated that the risk of HDP, preterm birth and low birth weight was higher after FET protocols with no corpus luteum (programmed FET) compared with pregnancies after FET protocols creating a corpus luteum (tNC-FET). Moreover, grouped by the BMI of patients, programmed FET group compared with the tNC-FET group, we showed a tendency toward increasing risk of HDP, preterm birth and low birth weight as the weight of the patient increases.
A large epidemiologic study by Saito et al in Japan examined the risk for HPD in autologous pregnancies regarding the FET protocols used natural cycle (n=29,760) and programmed cycle (n=75,474). They determined that compared with a natural-cycle FET, pregnancies after programmed FET had increased odds of HPD (adjusted OR, 95% CI 1.43[1.14–1.80]). In our study, the risk of HDP (adjusted OR, 95% CI 1.845 [1.031-3.300]) was also increased in programmed FET group compared with the tNC-FET group. Otherwise, we also showed a tendency toward increasing risk of preterm birth and low birth weight, it may be related to increased risk of HPD. After we excluded HPD in the regression analysis, the increased risk of preterm birth and low birth weight was not present (Supplementary Table 1).
Estrogen and progesterone are essential for the development of a normal placenta during pregnancy. Altered levels of these sex steroid hormones may lead to placenta-related complications in programmed FET cycle. Due to failure of normal decidualization and excessive invasion of trophoblasts, low progesterone levels in early pregnancy may lead to placental implantation. In contrast, some studies have shown that later development of pre-eclampsia is associated with high progesterone in early third trimester. A recent overview has been shown that FET cycles have been associated with an increased risk for adverse obstetric and perinatal outcomes of a pregnancy, the absence of the CL and the following deficient circulatory adaptations during early pregnancy in programmed cycles may play a role in these increased risk. The CL is an important source of reproductive hormones before the establishment of the placenta as a source of pregnancy maintaining reproductive hormones, such as progesterone and estrogen. Moreover, CL also produces vasoactive products such as relaxin, vascular endothelial growth factor (VEGF), and angiogenic metabolites of estrogen. They are also key factors in pregnancy maintenance. The vasoactive products produced by CL are thought to play an important role in early placenta formation and maternal circulation adaptation, and abnormal early placenta is often considered to be a key step in the development of preeclampsia .
BMI also have important influence in IVF/ICSI outcomes. The adverse effects of overweight/obesity on pregnancy outcomes have been widely confirmed, including dysregulation of the hypothalamic-pituitary-ovarian axis, ovulation disorders, impaired preimplantation embryo, and higher risk of miscarriage. Meanwhile, pre-pregnancy overweight and obesity are related to many adverse obstetric and perinatal outcomes of a pregnancy, including HPD, GDM, fetal macrosomia, fetal structural anomalies, CS, preterm delivery and low neonatal Apgar score[23–26]. A recent study in Korean women demonstrated that pre-pregnancy overweight and obesity are more closely related to the adverse obstetric outcomes than excess weight gain during pregnancy. In our study, considering the important impact of BMI on obstetric and perinatal outcomes of a pregnancy, we further grouped patients according to their pre-pregnancy BMI. We demonstrate that the risk of HDP in obese patients was increased in programmed FET group compared with the tNC-FET group. And a tendency toward increasing risk of HDP as the weight of the patient increases was observed. The increased risk of preterm and low birth weight has also been observed, and through further analysis we believe that it is related to the increased risk of HPD (Supplementary Table 2). PCOS/anovulation also need to be focused. In the Swedish study, the investigators adjusted for anovulation, and the Chinese study included only normoovulatory women both found a higher risk of HDP. We were not able to adjust for PCOS/anovulation; however, analyses excluding all women with PCOS/anovulation did not change our results (Supplementary Table 3).
An increased risk of macrosomia in the programmed FET group was also found in the Swedish study. Reasons for the increased risk of high birth weight in pregnancy after FET include maternal factors[27, 28], embryo culture media[29, 30], embryo transfer status (cleavage stage/blastocyst)[7, 31], and the quality of transferred embryos during FET. Our study also shows a tendency toward increasing risk of macrosomia. Recent study also showed that the freezing/thawing process (both slow freeze and verification) may cause epigenetic changes, which may be related to newborn weight gain [32, 33]. In addition, some studies have shown that the risk of adverse obstetric and perinatal outcomes of a pregnancy such as CS increases after in the programmed FET group[16, 34]. In our study, the risk of cesarean section dose not increase in the programmed FET group significantly, but the rate of CS has showed higher in programmed FET group (72.9%) than tNC-FET group (68%). The higher risk of adverse obstetric and perinatal outcomes after the programmed FET treatment may be responsible for the higher risk of CS.
A major strength of this study is the complete birth cohort of singletons conceived after FET in China, which minimizes the risk of selection bias. In the multiple logistic regression analysis, we were able to adjust for maternal age, infertility duration, cause of infertility, BMI, endometrial thickness and high-quality embryo transfer rate. Considering the influence of BMI on obstetric and perinatal outcomes of a pregnancy, we further grouped according to BMI, firstly. Women treated with hCG trigger during FET cycle was not included in our study, because the key information absence, which is a main limitation of our study. The further study about programmed FET mNC-FET and tNC-FET should be performed in Chinese population.